Coated nicotine-containing chewing gum, manufacture and use thereof

ABSTRACT

A coated chewing gum product for the delivering of nicotine in any form to a subject by a rapid transmucosal uptake in the oral cavity comprising at least one gum core, nicotine in any form and/or a nicotine mimicking agent, at least one coating layer and optionally at least one or more other additive, wherein said at last one coating layer is buffered. Also contemplated is a method for the delivering of nicotine in any form, a method for the reduction of the urge to smoke or use tobacco as well as a method for producing said coated chewing gum and the use of the same form obtaining a quick transmucosal uptake of the nicotine in the oral cavity of a subject.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application is the national stage filing under 35 U.S.C. §371 of International Application No. PCT/SE02/01158 filed Jun. 14, 2002and published Dec. 27, 2002, as International Publication No. WO02/102357 which in turn claims priority under 35 U.S.C. § 119 to SwedishPatent Application No. 0102197, filed Jun. 20, 2001. The disclosures ofthese applications are incorporated herein by reference in theirentirety.

FIELD

[0002] This invention relates to a coated chewing gum product fordelivering nicotine to a subject. Also contemplated is a method and asystem for delivering nicotine as well as use and production of saidcoated chewing gum product

BACKGROUND

[0003] Tobacco Dependence and Reduction Thereof.

[0004] In recent years, with the recognition of the harmful effects oftobacco smoking, there have been numerous campaigns and programs bygovernmental agencies and various health groups and other interestedorganisations to disseminate information about the adverse healtheffects resulting from tobacco smoking. Moreover, and as a result ofthis recognition of the harmful effects, there have been many programsdirected to attempts in reducing smoking incidence.

[0005] Nicotine is an organic compound and is the principal alkaloid oftobacco. Nicotine is the chief addictive ingredient in the tobacco usedin cigarettes, cigars, snuff and the like. Nicotine is also an addictivedrug, though, and smokers characteristically display a strong tendencyto relapse after having successfully stopped smoking for a time.Nicotine is the worlds second most used drug, after caffeine from coffeeand tea.

[0006] The main problem with tobacco smoking is its enormousimplications on health. Today it is estimated that smoking relateddiseases cause some 3-4 million deaths per year. In the US SurgeonGeneral's 1988 report on The Health Consequences of Smoking, it wasestimated that in the US alone about 300.000 deaths are caused each yearby diseases related to cigarette smoking. In fact, excessive smoking isnow recognised as one of the major health problems throughout the world.This grim consequence of tobacco smoking has urged many medicalassociations and health authorities to take very strong actions againstthe use of tobacco.

[0007] Even though tobacco smoking is decreasing in many developedcountries today it is hard to see how the societies could get rid of theworld's second most used drug.

[0008] The most advantageous thing a heavy smoker can do is to reduce orpreferably even stop smoking completely. Experience shows, however, thatmost smokers find this extremely difficult since, mostly, tobaccosmoking results in a dependence disorder or craving. The WHO has in itsInternational Classification of Disorders a diagnosis called TobaccoDependence. Others like the American Psychiatric Association call theaddiction Nicotine Dependence. It is generally accepted that thesedifficulties to stop smoking result from the fact those heavy smokersare dependent on nicotine. The most important risk factors are, however,substances that are formed during the combustion of tobacco, such ascarbon monoxide, tar products, aldehydes, and hydrocyanic acid.

[0009] Effects of Nicotine

[0010] The administration of nicotine can give satisfaction and theusual method is by smoking, either by smoking e.g., a cigarette, a cigaror a pipe. However, smoking has health hazards and it is thereforedesirable to formulate an alternative way of administering nicotine in apleasurable manner that can be used to facilitate withdrawal fromsmoking and/or used as a replacement for smoking.

[0011] When smoking a cigarette, nicotine is quickly absorbed into thesmoker's blood and reaches the brain within around ten seconds afterinhalation. The quick uptake of nicotine gives the consumer a rapidsatisfaction, or kick. The satisfaction, then, lasts during the smokingtime of the cigarette and for a period of time thereafter. Thepoisonous, toxic, carcinogenic, and addictive nature of smoking hasprovided efforts for methods, compositions and devices, which help inbreaking the habit of smoking cigarettes.

[0012] Nicotine is an addictive poisonous alkaloid C₅H₄NC₄H₇NCH₃,derived from the tobacco plant. Nicotine is also used as an insecticide.Approximately forty milligrams of nicotine is able to kill an adult(Merck Index).

[0013] Nicotine Replacement Products

[0014] One way to reduce smoking is to provide nicotine in a form ormanner other than by smoking and some products have been developed tofulfil this need. Nicotine containing formulations are currently thedominating treatments for tobacco dependence.

[0015] The successes in achieving reduction in the incidence of smokinghave been relatively poor using presently known products. The presentstate of the art involves both behavioural approaches andpharmacological approaches. More than 80% of the tobacco smokers whoinitially quit smoking after using some behavioural or pharmacologicalapproach to singly reduce smoking incidence generally relapse and returnto the habit of smoking at their former rate of smoking within about aone year's period of time.

[0016] As an aid for those who are willing to stop smoking there areseveral ways and forms of nicotine replacement products available on themarket; such as nicotine chewing gum. Several methods and means havebeen described for diminishing the desire of a subject to use tobacco,which comprises the step of administering to the subject nicotine or aderivative thereof as described in e.g., U.S. Pat. No. 5,810,018 (oralnicotine spray), U.S. Pat. No. 5,939,100 (nicotine containingmicrospheres) and U.S. Pat. No. 4,967,773 (nicotine containing lozenge).

[0017] Nicotine-containing nose drops have been reported (Russell etal., British Medical Journal, Vol. 286, p. 683 (1983); Jarvis et al.,Brit. J. of Addiction, Vol. 82, p. 983 (1987)). Nose drops, however, aredifficult to administer and are not convenient for use at work or inother public situations. Ways of administrating nicotine by way ofdelivering directly into the nasal cavity by spraying is known from U.S.Pat. No. 4,579,858, German Patent No. 32 41 437 and InternationalPublication No. WO/9312764. There may, though, be local nasal irritationwith use of nasal nicotine formulations. The difficulty inadministration also results in unpredictability of the dose of nicotineadministered.

[0018] The use of skin patches for transdermal administration ofnicotine has been reported (Rose, in Pharmacologic Treatment of TobaccoDependence, (1986) pp. 158-166, Harvard Univ. Press).Nicotine-containing skin patches that are in wide use today can causelocal irritation and the absorption of nicotine is slow and affected bycutaneous blood flow.

[0019] Also, inhaling devices resembling a cigarette are known foruptake of nicotine vapours as suggested in U.S. Pat. No. 5,167,242. Saidmeans and methods address the problems associated with addiction tonicotine.

[0020] Nicotine Chewing Gum

[0021] One of the most successful approaches to date in reducing theincidence of smoking relies upon nicotine containing chewing gum that isdesigned to reduce smoking withdrawal symptoms. The reported successrate is approximately twice that of placebo. The use of the nicotine gumsuffers from several problems e.g., that it has been found that thenicotine containing gum does not sufficiently rapidly satisfy thecraving that most smokers experience.

[0022] Prior Art and Problems Thereof

[0023] One successful product that is used as a smoking substituteand/or as a smoking cessation aid and which is based on nicotine, is thechewing gum Nicorette®. This product was one of the first nicotinereplacement forms that was approved by the Food and Drug Administration(FDA) and is still one of the most used nicotine replacement products.Nicorette® chewing gum has been on the market in about 60 countries forseveral years. In this chewing gum the nicotine is present in the formof a complex with an insoluble cation-exchanger (polacrilex) that isdispersed in a gum base. The nicotine is slowly released from the gumdue to chewing and will reach similar plasma levels as when smoking acigarette after about 30 minutes depending on the chewing technique,i.e., slow or active. Patents related to this product are, e.g., theU.S. Pat. Nos. 3,877,468, 3,901,248 and 3,845,217.

[0024] WO 98/23165 discloses a chewing gum wherein nicotine may be inthe coating. This concept may provide rapid release of the nicotine fromthe coated chewing gum, but not a sufficiently rapid buccal uptake ofthe nicotine. The fraction of the released nicotine that is notimmediately absorbed will be flushed down in the gastrointestinal (G.I.)tracts by the saliva, thereby possibly causing hiccups and other G.I.side effects. Once absorbed by the G.I. route this swallowed nicotinewill be subjected to first pass metabolism.

[0025] WO 00/13662 discloses a chewing gum for systemic, oraladministration of an active whereby said active is administered by thechewing gum composition in a bi-phasic manner. The bi-phasic delivery isobtained by the gum matrix as such, not from any coating.

[0026] WO 00/19977 discloses a substantially moisture free and possiblycoated chewing gum for delivery of an active. The possible coating isnot said to be buffered.

[0027] It is highly desirable in light of the aforementioned problems todevelop means and methods for the administration of nicotine to give asatisfaction to a person craving for nicotine or to provide a sense ofsmoking satisfaction without smoking, which can also avoid problemsassociated with the prior art means and methods. In this respect, thepresent invention addresses this need and interest.

SUMMARY

[0028] In view of the foregoing disadvantages known in the art whentrying to deliver nicotine to a subject so as to obtain a rapidtransmucosal uptake of nicotine in the oral cavity of the subject thepresent invention provides a new and improved product, systems andmethods for obtaining a rapid transmucosal uptake of nicotine in theoral cavity of the subject.

[0029] An object of the present invention is to provide an efficient andeffective product, as well as methods and systems for a rapid uptake ofnicotine in a subject to avoid the disadvantages of such previouslyknown products and methods.

[0030] Thus, the present invention provides a method for deliveringnicotine in any form to a subject comprising administering to a subjectsaid coated chewing gum product containing nicotine in any form into theoral cavity of the subject and allowing the nicotine in any form in thecoated chewing gum product to be released in the saliva in the oralcavity and absorbed into the systemic circulation of the subject as wellas a method for producing said coated chewing gum.

[0031] The present invention also provides a method for obtainingreduction of the urge to smoke or use tobacco containing material and/orfor providing a sense of smoking satisfaction without smoking,comprising the steps of replacing at least partly the tobacco containingmaterial with above said coated chewing gum product, administering to asubject a coated chewing gum product containing nicotine in any forminto the oral cavity of the subject and allowing the nicotine in anyform of the coated chewing gum product to be released in the saliva inthe oral cavity and absorbed by the subject.

[0032] Furthermore, the present invention provides a system fordelivering nicotine in any form to a subject, comprising said coatedchewing gum product and at least one other means for obtaining reductionof the urge to smoke or use of tobacco as well as a system for obtainingreduction of the urge to smoke or otherwise use of tobacco and/or forproviding a sense of smoking satisfaction without smoking, comprising acoated chewing gum product according to above and at least one othermethod for obtaining reduction of the urge to smoke or otherwise use oftobacco. Said system may be a system wherein the at least other methodis selected from the group consisting of administration through mouthsprays, nasal sprays, transdermal patches, inhaling devices, lozenges,tablets and parenteral methods, subcutaneous methods, intravenousmethods, rectal methods, vaginal methods and transmucousal methods; orotherwise use of tobacco.

[0033] Still furthermore the present invention relates to a coatedchewing gum product comprising at least one chewing gum core, nicotinein any form and/or a nicotine mimicking agent, at least one coatinglayer and optionally at least one or more other additive, wherein saidat least one coating layer is buffered.

[0034] Said product may further comprise at least one core beingbuffered and further may also the nicotine in any form be a part of theat least one coating layer or at least one of the at least one coatinglayers. The at least one coating is buffered, according to theinvention, in such a way that upon administration of the gum the pH ofthe saliva is increased by 0.3-4 pH units, or preferably increased by0.5-2 pH units. Said product is buffered by the use of a buffer selectedfrom the group consisting of a carbonate, including bicarbonate orsesquicarbonate, glycinate, phosphate, glycerophosphate or citrate of analkali metal, such as potassium and sodium, e.g., trisodium andtripotassium citrate, or ammonium, and mixtures thereof.

[0035] Use of said product will according to the invention rapidlydeliver nicotine in any form to a subject and will also be used forobtaining a quick and/or sustained and/or complete reduction of the urgeto smoke or use tobacco and/or for providing a sense of smokingsatisfaction without smoking resembling the sense of smokingsatisfaction and reduction of the urge to smoke obtained after regularsmoking or use of tobacco.

DETAILED DESCRIPTION

[0036] Definitions

[0037] As used herein, the term “chewing gum product” intends to meanall chewable gum products.

[0038] The term “fast reduction of the urge to smoke or use tobacco” isherein intended to mean an initial priming of the subject so as toachieve a reduction of the urge to smoke or use tobacco.

[0039] The term “sustained” is herein intended to mean prolonged overtime.

[0040] The term “complete reduction” or “complete” is herein intended tomean complete or substantially complete reduction.

[0041] The term “controlled release” is intended to mean a release of asubstance from a gum by the aid of active chewing of the gum in the oralcavity of the subject, whereby the active chewing is controlling theamount of substance released.

[0042] The term “slow release” is intended to mean that the nicotine isreleased from the gum upon, e.g., chewing, over a period of time e.g.,several minutes to an hour.

[0043] The term “unit formula” is intended to mean one chewing gumproduct.

[0044] The term “transient” is intended to mean a non-permanent change,upon which the relevant state, e.g., biological or physiological state,after a certain period of time will return to its value or behaviourprior to said change.

[0045] The term “buccal” and “buccally” are herein intended to pertainto all of or any part of the tissue of the oral cavity.

[0046] The Coated Chewing Gum

[0047] Presently existing nicotine chewing gums provide a slow releaseand a slow uptake of nicotine. This will not resemble the actual senseof satisfaction when smoking, where an initial fast uptake of nicotineis achieved giving the smoker, i.e., the subject, a sense ofsatisfaction. Accordingly, as revealed above, the present inventionrelates to a coated chewing gum product for improving the absorption ofnicotine in a subject, and wherein the absorption is quicker than byusing current means and methods known in the art of nicotine chewinggums. Such a rapid transmucosal uptake of the nicotine in the oralcavity is expected to give more of a cigarette like sense ofsatisfaction and a more rapid reduction of the urge to smoke and usetobacco.

[0048] According to the invention, a coated chewing gum product is usedfor improving the absorption of said nicotine. The coated chewing gumproduct comprises at least one chewing gum core, nicotine in any formand/or a nicotine mimicking agent, at least one coating layer and atleast one other additive, wherein at least one of said coating layer isbuffered.

[0049] Also, the at least one core may be buffered in differentembodiments. The core may be buffered with the same or different ways ofbuffering as the at least one coating layer.

[0050] Said buffering of the at least one coating layer and optionallythe at least one core generates a coated chewing gum product givingimproved absorption kinetics of nicotine compared to in the art knownchewing gum products.

[0051] The chewing gum product may be a medicated chewing gum. Medicatedchewing gums are herein intended to mean solid or semi-solid,single-dose preparations with a base consisting mainly of gum that areintended to be chewed but not swallowed, where the chewing gums act as adrug delivery system. They contain one or more active substances, whichare released by chewing. After dissolution or dispersion of the activesubstance in the saliva, such chewing gums are used for i) localtreatment of mouth diseases and ii) systemic delivery after absorptionthrough transmucosal uptake throughout the oral cavity.

[0052] The Buffering Agent

[0053] Absorption of nicotine from the oral cavity to the systemiccirculation is dependent on the pH of the saliva, pH of the blood plasmaand the pKa of nicotine, which is about 7.8. Assuming a pH of the plasmaof 7.4 and of the saliva of 6.8 only about 10% of the nicotine will bein the free base form. Thus, in order to promote absorption of nicotinein a free base form, which is the form predominantly absorbed throughthe mucosa, the pH of the saliva must be increased. At a pH of 8.8 about90% of the nicotine will then be in the free base form.

[0054] Thus according to the invention, the coated chewing gum productis buffered. This may be achieved by including physiologicallyacceptable buffering substances or agents, or by other means. With othermeans it is intended to include buffering by any component in theproduct, which may not normally act as a buffering agent, such as aself-buffering additive or gum base.

[0055] According to the invention, at least one coating layer isbuffered. In specific embodiments, also the at least one core isbuffered.

[0056] In specific embodiments, the at least one coating layer isbuffered in such a way that upon administration of the gum the pH of thesaliva is increased 0.3-4 pH units, preferably 0.5-2 pH units. Thebuffering is designed so as to achieve a transient buffering of thesaliva of a subject during melting, disintegration or dissolution of thecoating layer or layers. As the change is transient, the pH will returnto its normal value after a certain period of time.

[0057] Similarly, the at least one core may be buffered. This may allowsaid change in the pH to be ensured during chewing of the core of thegum product, where the chewing allows the suitable buffer agent orsubstance or other means to produce a transient change in the pH of thesaliva, e.g., an increase in the pH.

[0058] By employing the said change, here as an increase, in said pH ofthe saliva the transmucosal uptake of nicotine in the oral cavity ischanged, e.g., increased compared to the nicotine uptake when the salivais not buffered according to the invention. Also, since the transmucosaluptake of nicotine in the oral cavity according to the invention isfaster than for nicotine not being buffered according to the invention,less nicotine will be swallowed to reach the gastrointestinal (G.I.)tract. The nicotine that reaches the G.I. tract will be subjected tofirst pass metabolism which reduces the total amount of intact nicotineabsorbed. This means that the bio-availability of nicotine that is notco-administered with a buffer according to the invention will generallybe lower than when administered together with a buffer.

[0059] Further embodiments of the invention includes combinationswherein the at least one coating layer is buffered by the use of abuffer selected from the group consisting of a carbonate includingbicarbonate or sesquicarbonate, glycinate, phosphate, glycerophosphateor citrate of an alkali metal, such as potassium or sodium, or ammonium,and mixtures thereof.

[0060] Further embodiments may use trisodium or tripotassium citrate,and mixtures thereof.

[0061] Still further embodiments may use different phosphate systems,such as trisodium phosphate, disodium hydrogen phosphate; andtripotassium phosphate, dipotassium hydrogen phosphate, and calciumhydroxide, sodium glycinate; and mixtures thereof.

[0062] Alkali metal carbonates, glycinates and phosphates are preferredbuffering agents.

[0063] The one or more buffering agents may to some extent bemicroencapsulated or otherwise coated as granules with polymers and/orlipids being less soluble in saliva than is the one or more bufferingagents. Such microencapsulation controls the dissolution rate whereby isextended the time frame of the buffering effect.

[0064] In order to increase the buffering capacity still further withoutcorrespondingly increasing the pH, one may in specific embodiments use asecond or auxiliary buffering agent to the first buffering agent, suchas e.g., sodium or potassium bicarbonate buffers. The second orauxiliary buffering agent may be selected from the group consisting ofalkali metal bicarbonates that are preferred for this purpose. Thus,further embodiments of the invention may comprise a mixture of an alkalimetal carbonate or phosphate and alkali metal bicarbonate.

[0065] The amount of the buffering agent or agents in the chewing gumcomposition is preferably sufficient in the specific embodiments toraise the pH of the saliva to above 7, as specified above, totransiently maintain the pH of the saliva in the oral cavity above 7,e.g., pH 7-11.

[0066] The nicotine may be administered in different forms, e.g., indifferent complexes or salts. The amount of buffer required to achievesuch an increase in pH of the different administered nicotine form isreadily calculated by the skilled man in the art. The extent andduration of the increase in pH is dependent on type and amount of thebuffering agent(s) used as well as where, i.e., in the at least onecoating layer and optionally in the at least one core, the buffer isdistributed in the product and is further described within theparagraphs below.

[0067] The Coating of the Gum Core

[0068] The process of coating a chewing gum is well known in the art.The present invention provides a coating, to facilitate the uptake ofadministered nicotine in any form to the subject. Known intentions ofcoating a chewing gum product may be to add crispiness, enhance taste,or to protect the gum, e.g., during storage, or as to tone down bad orirritating taste of the gum product.

[0069] According to the invention, the chewing gum is a coated chewinggum comprising at least one coating layer.

[0070] The different embodiments according to the invention may usesugar coating, film coating, press/compression coating or melt coating.

[0071] For the film and sugar coating, the coating procedure may bemanual or the coating may be sprayed onto the gum core/pellet inrotating pans of different shapes or fluidised beds in combination withevaporation of the solvent, e.g., water or organic solvent.

[0072] Sugar coating is a multistep process and may be divided into thefollowing steps: 1. sealing of the cores; 2. subcoating; 3. smoothing,or glossing; 4. colouring; 5. polishing; and 6. optionally printing

[0073] Sugar coated cores have a smoother profile with less visibleedges remaining from the original core. Sub-coating, e.g., either bydusting with powder on the sucrose solution or application of dry powderin the sucrose solution, may be used. The core may be sugar coated by apanning technique, e.g., using a sugar coating pan, or other moresophisticated techniques capable of some degree of automation.

[0074] The sugar in a sugar coating may not be just sucrose. Also othertypes of sugar may do as well, e.g., sugar alcohols (polyalcohol,polyol).

[0075] The sugar used in the sugar coating may according to specificembodiments also be an artificial sweetener, being low or substantiallyfree of calories and less caries promoting than regular sugar, or acombination with sugar and/or sugar alcohol.

[0076] Film coating involves the deposition, usually by a spray method,of a thin film of polymer surrounding the core. The solution may besprayed on to a rotated, mixed bed. The drying conditions permit theremoval of the solvent so as to leave a thin deposition of coatingmaterial around each core.

[0077] The composition of the coating solutions and suspensions maydiffer during different parts of the process.

[0078] Press coating involves the compaction of granular material aroundan already manufactured core. Using press/compression coating, a furthercore is pressed on the outside of the initial core/cores.

[0079] Example 1-4 describes four different coatings and coatingcompositions that may be used according to the invention, i.e., sugarcoating in example 1, film coating in example 2, press coating inexample 3 and melt coating in example 4, all onto a chewing gum core.The coating is buffered in each case and contains nicotine as well. Thecoatings in example 1-4 may be combined with different cores. Examplesof cores are given in Example 5 and further described below.

[0080] If nicotine hydrogen tartrate (NHT) is used as the nicotine formthen NHT and buffer are suitably separated from each other in thecoating by keeping them in separate layers, especially when sugarcoating is used. A moisture barrier between the NHT-containing layer andthe coating comprising the buffer may be applied to prevent interactionbetween the acid salt NHT and the buffer during the coating process.Suitable moisture barriers are e.g. ethylcellulose or a combination ofethylcellulose and hydroxypropyl methylcellulose (HPMC) and/orplasticizer from an organic solvent or solvent mixture, aqueousethylcellulose dispersion such as Aquacoat EDC (FMC Corp.) or Surelease(Colorcon) preferably in combination with plasticizer, Sepifilm LP 007or LP 010 (Seppic)—based mainly on HPMC and stearic acid—, Opadry AMB orHigh Performance Opadry II (Colorcon)—based mainly on polyvinylalcohol—,and polymethacrylates as Eudragit L30 D-55 or EPO (Röhm). Depending onthe type of barrier film selected the moisture barrier preferablyaccounts for a weight of around 0.3% to around 5% of the total weight ofthe coating.

[0081] An additive may be added to the coating or the core/s. Additivesare further described in the paragraph entitled “Other additives to thechewing gum”.

[0082] The Core

[0083] The amount of gum base in the coated chewing gum according to theinvention is about 15-80% by weight of the total gum core, andpreferably at least about 40%. The amount of gum base employed for themost desirable slow release of nicotine is usually in the higher rangeswhen nicotine is employed per se or when an absorbed form is used.

[0084] The gum base may be of any conventional nature known in the art.For example it may comprise a gum base of natural or synthetic originreadily available from a commercial source. Natural gum bases include,e.g., chicle, jelutong-, lechi de caspi-, soh-, siak-, katiau-, sorwa-,balata-, pendare-, malaya-, and peach gums, natural cautchouc andnatural resins such as dammar and mastix. Synthetic gum bases are amixture of:

[0085] elastomers (polymers, masticating substances),

[0086] plasticizer (resin, elastomers, solvent, hydrophobic resin),

[0087] filler (texturizer, water-insoluble adjuvant),

[0088] softener (fat),

[0089] emulsifier,

[0090] wax,

[0091] antioxidant,

[0092] and anti-tacking agents (vinyl polymer, hydrophilic resin).

[0093] Other examples of gum bases are gums including agar, alginate,arabic gum, carob gum, carrageenan, ghatti gum, guar gum, karaya gum,pectin, tragacanth gum, locust beam gum, gellan gum and xanthan gum.

[0094] Examples of gelling agents comprise gum arabic, starch, gelatine,agar, and pectin.

[0095] When the nicotine in any form and the buffering agent or agentsare incorporated in the chewing gum mass in accordance with the presentinvention, it is possible to employ a wide variety of chewing gumcompositions and amounts of the chewing gum base. Different chewing gumproducts may be composed depending on the consumers preference and thepurpose of use, in respect of the nicotine level, nicotine distributionand other additives.

[0096] The Active Ingredient

[0097] According to the invention, the chewing gum product comprisesnicotine in any form and/or a nicotine mimicking agent. In specificembodiments, the nicotine is part of the at least one coating layer orat least one of the at least one coating layers.

[0098] In still further embodiments, the nicotine is a part of thechewing gum core or at least one of the chewing gum cores.

[0099] In still even further embodiments, the nicotine is part of the atleast one coating layer or at least one of the at least one coatinglayers and the chewing gum core or at least one of the chewing gum coresto give a fast transmucosal uptake of the nicotine in the oral cavity ofa subject so as to obtain a rapid kick or reduction of the urge to smokeand/or use tobacco. Thereby may also be achieved a systemic maintenancelevel of nicotine.

[0100] The nicotine should be in a saliva soluble form to facilitate therelease of the agent into the saliva in the oral cavity and, further,the subsequent uptake of the nicotine from the saliva in the oral cavityinto the systemic circulation of the subject.

[0101] In preferred embodiments, the nicotine in any form is selectedfrom the group consisting of a nicotine salt, the free base form ofnicotine, a nicotine derivative, such as a nicotine cation exchanger, anicotine inclusion complex or nicotine in any non-covalent binding;nicotine bound to zeolites; nicotine bound to cellulose or starchmicrospheres; and mixtures thereof. Still, further the inclusion complexmay be a cyclodextrin, such as β-cyclodextrin. Even further the cationexchanger may be a polyacrylate. Even more further, the nicotine saltmay be a tartrate, hydrogen tartrate, citrate or malate.

[0102] According to the invention, the uptake of the nicotine throughany tissue or mucosa in the oral cavity, i.e., the absorption kinetics,is improved in relation to the uptake obtained by known chewing gumproducts for nicotine uptake.

[0103] The nicotine may act as a stimulant to e.g., obtain a rapidreduction of the urge to smoke or to use tobacco.

[0104] With nicotine it is intended to include nicotine,3-(1-methyl-2-pyrrolidinyl)-pyridine, with its base form, includingsynthetic nicotine as well as nicotine extracts from tobacco plants, orparts thereof, such as the genus Nicotiana alone or in combination; orpharmaceutically acceptable salts.

[0105] The most preferable embodiment incorporates nicotine as the freebase form or as a water-soluble pharmaceutically acceptable salt, eitherper se or adsorbed on a adsorbent, or as a complex with a cationexchanger or mixtures of the foregoing, as an inclusion complex, such asa cyclodextrin complex, e.g., β-cyclodextrin, but any other suitablepharmaceutically acceptable form may also be employed.

[0106] Numerous nicotine salts are known, and may be used, e.g., thesalts presented in Table 1, such as preferably the tartrate, hydrogentartrate, citrate, malate, and/or hydrochloride. TABLE 1 Possible acidsused for nicotine salt formation Molar ratio* of Acid acid:nicotineFormic 2:1 Acetic 3:1 Propionic 3:1 Butyric 3:1 2-Methylbutyric 3:13-Methylbutyric 3:1 Valeric 3:1 Lauric 3:1 Palmitic 3:1 Tartaric 2:1Citric 2:1 Malic 2:1 Oxalic 2:1 Benzoic 1:1 Gentisic 1:1 Gallic 1:1Phenylacetic 3:1 Salicylic 1:1 Phthalic 1:1 Picric 2:1 Sulfosalicylic1:1 Tannic 1:5 Pectic 1:3 Alginic 1:2 Hydrochloric 2:1 Chloroplatinic1:1 Silicotungstic 1:1 Pyruvic 2:1 Glutamic 1:1 Aspartic 1:1

[0107] The product according to the invention may also comprise anicotine mimicking agent. Such an agent may be any suitable agent withan acrid burning taste. Examples of nicotine mimicking agents with anacrid burning taste are capsaicin, piperine and zingerone.

[0108] One or more additives may be added to the coating or the core/s.Additives are further described in the paragraph entitled “Otheradditives to the chewing gum”.

[0109] Amount and Distribution of the Nicotine in the Coated Chewing Gum

[0110] The nicotine in any form is according to the invention formulatedto provide the subject with a dose to achieve an effect. The effect maybe to provide a sense of smoking satisfaction without smoking. Anothereffect of the administered nicotine in any form may be a reduction ofthe urge to smoke or use tobacco.

[0111] The effect may also be a combination of reduction of said urgeand providing a sense of smoking satisfaction without smoking. Theamount of the nicotine should be sufficient to provide such an effect ina subject. This amount may, of course, vary from person to person.

[0112] According to the invention, embodiments of the chewable gumproduct comprise embodiments wherein nicotine in any form is present inan amount of 0.05-10 mg calculated as the free base form of nicotine perpiece coated chewing gum product. This may in different embodimentsinclude 0.05, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg calculated as thefree base form of nicotine per piece coated chewing gum product.

[0113] Still preferred embodiments may contain embodiments where thenicotine in any form is present in an amount of 0.5-6 mg calculated asthe free base form of nicotine per piece coated chewing gum product.

[0114] Even more preferred embodiments contain the nicotine in any formin an amount of 0.5-4 mg calculated as the free base form of nicotineper piece coated chewing gum product.

[0115] According to certain embodiments of the invention, the nicotinein any form is part of the at least one coating layer or at least one ofthe at least one coating layer.

[0116] The nicotine in any form may be in an amount of 0-10 mgcalculated as free base form in at least one of the at least one coatinglayer. Still further embodiments comprise nicotine in an amount of 0.2-6mg in at least one of the at least one coating layers, or even morepreferably, in an amount of 0.5-5 mg in at least one of the at least onecoating layer.

[0117] The nicotine in any form may be distributed in the core and/ordifferent coating layers in different embodiments. Differentdistributions of the nicotine throughout the coated chewing gum willimply administration of the nicotine to the subject in different ways.This may, then, provide several possibilities to adjust the compositionof the coated chewing gum according to different needs of differentsubjects depending on the urge to smoke or use tobacco of the subject.

[0118] Release and Uptake of Nicotine

[0119] Presently existing nicotine chewing gums provide a slow releaseand a slow uptake of the nicotine compared to smoking. The slow uptakeof the nicotine provides a t_(max), i.e., the time-point where thenicotine has its maximum level measured in the plasma of venous blood,after a single dose at about 30 minutes after administration. Thet_(max) is initially preceded by a lag period of a couple of minuteswhere no nicotine can be detected in the blood. Then, the plasma levelis gradually increasing till the t_(max) is reached.

[0120] The time point for reaching a sense of satisfaction or reductionof urge to smoke or use tobacco after the initial lag period isindividual, but may in existing chewing gums generally be reached afterapproximately 30 minutes when regarded as coinciding with t_(max).According to the present invention, such a sense of satisfaction may bereached after a shorter period of time due to a rapid initial burst doseof nicotine in the coating followed by a rapid transmucosal uptake inthe oral cavity due to the buffered coating.

[0121] The release of the nicotine in the coated chewing gum accordingto the invention proceeds in at least one step.

[0122] I) If the nicotine is, as in preferred embodiments, in a definedamount, such as the amounts described above according to differentembodiments, in at least one of the at least one coating layers definedabove the release of the nicotine takes place when the coating of thecoated chewing gum is allowed to melt, disintegrate or dissolve touncover the chewable gum core in said product. The nicotine and formsthereof is released from the coating into the saliva in the oral cavityduring the time period when the coating is allowed to melt, disintegrateor dissolve.

[0123] When the at least one coating layer is allowed to melt,disintegrate or dissolute a chewable gum is uncovered. The nicotine inany form may then further be released to the subject.

[0124] II) The nicotine in any form from the chewable gum is released bycontrolled release, e.g., by chewing the gum core whereby the chewing iscontrolling the amount of released nicotine from the gum core. Therelease of the nicotine is thereby sustained over a period of time. Thisperiod of time may be, in different embodiments about 10, 20, 30, 40,50, or 60 minutes.

[0125] The dissolution of the one or more buffering agents in thecoating, and optionally in the core(s), provides for optimizedadjustment of the pH of the liquid in the oral cavity.

[0126] The release may be varied by the incorporation of the nicotine inany form in a given quantity into the coating layers and/or the gumcore.

[0127] Suitable cat ion exchangers are given in table 2 and are furtherdisclosed in U.S. Pat. No. 3,845,217, hereby included as a reference.Preferred are nicotine cation exchangers of polyacrylates, such as theAmberlite collection from Rohm & Haas in table 2. Examples of differentsalts are given in Table 1. TABLE 2 Representative cation exchangersName Manufacturer Amberlite IRC 50 Rohm & Haas Amberlite IRP 64 Rohm &Haas Amberlite IRP 64M Rohm & Haas BIO-REX 70 BIO-RAD Lab. Amberlite IR118 Rohm & Haas Amberlite IRP 69 Rohm & Haas Amberlite IRP 69M Rohm &Haas BIO-REX 40 BIO-RAD Lab. Amberlite IR 120 Rohm & Haas Dowex 50 DowChemical Dowex 50W Dow Chemical Duolite C 25 Chemical Process Co LewatitS 100 Farbenfabriken Bayer Ionac C 240 Ionac Chem. Wofatit KP S 200 I.G.Farben Wolfen Amberlyst 15 Rohm & Haas Duolite C-3 Chemical ProcessDuolite C-10 Chemical Process Lewatit KS Farbenfabriken Bayer. Zerolit215 The Permutit Co. Duolite ES-62 Chemical Process BIO-REX 63 BIO-RADLab. Duolite ES-63 Chemical Process Duolite ES-65 Chemical ProcessOhelex 100 BIO-RAD Lab. Dow Chelating Resin A-1 Dow Chemical CompanyPurolite C115HMR Purolite International Ltd. CM Sephadex C-25 PharmaciaFine Chemicals SE Sephadex C-25 Pharmacia Fine Chemicals

[0128] Not only the amount of the nicotine released from the differentparts of the chewing gum product is of value as known in the art, butalso, according to the present invention the specific transmucosaluptake from the oral cavity of the nicotine to the systemic circulationof the subject whereby the one or more buffering agents account forprovision of a suitable adjustment of the pH of the liquid of the oralcavity. The uptake according to the invention is further discussed inthe method paragraphs below.

[0129] Other Additives to the Chewing Gum

[0130] Other additives may be added optionally to the chewing gum coreand/or to coating layers in the chewing gum.

[0131] Optional additives comprise at least one or more additiveselected from the group consisting of stabilisers, such aspreservatives, e.g., antioxidants; softeners, thickening agents,emulsifiers, glidants, lubricants, sweeteners, flavours, aromatics,enhancers, colouring agents, vitamins, minerals, fluorine and toothwhitening agents and mixtures thereof. According to the invention, atleast one of such additives is optionally added to the product.

[0132] Enhancers are added essentially to improve, i.e., increase, thetransmucosal uptake from the oral cavity.

[0133] Sweeteners are added essentially to improve the taste.

[0134] Sweeteners comprise one or more synthetic or natural sugars,i.e., any form of carbohydrates suitable for use as sweetener, as wellas so called artificial sweeteners such as saccarin, sodium saccarin,aspartame, e.g., NutraSweet®, acesulfame K or acesulfame, potassiumacesulfame, thaumatin, glycyrrhizin, sucralose, dihydrochalcone,alitame, miraculin, monellin, stevside.

[0135] Suitable sweeteners may be selected from the group consisting ofsugar alcohols, such as sorbitol, xylitol, single sugars includingsugars extracted from sugar cane and sugar beet (sucrose), dextrose(also called glucose), fructose (also called leavulose), and lactose(also called milk sugar); sorbitol, mannitol, glycerol, xylitol,maltitol syrup (or hydrogenated starch hydrolyzate), isomalt, lactitol;and mixtures of sugars including glucose syrup, e.g., starchhydrolysates, containing a mixture of dextrose, maltose and a range ofcomplex sugars, invert sugar syrup, e.g., sucrose inverted by invertase(also called sucrase or sacchrase) containing a mixture of dextrose andfructose, high sugar content syrups such as treacle and honey containinga mixture of particular leavulose, dextrose, maltose, lactitole,sucrose, resins, dextrin and higher sugars; and malt or malt extracts.

[0136] The flavour and aroma additives may comprise one or moresynthetic or natural flavouring or aromatizing agents.

[0137] Flavour and aroma agents may be selected from essential oilsincluding distillations, solvent extractions, or cold expressions ofchopped flowers, leaves, peel or pulped whole fruit comprising mixturesof alcohols, esters, aldehydes and lactones; essences including eitherdiluted solutions of essential oils, or mixtures of synthetic chemicalsblended to match the natural flavour of the fruit, e.g., strawberry,raspberry and black currant; artificial and natural flavours of brewsand liquors, e.g., cognac, whisky, rum, gin, sherry, port, and wine;tobacco, coffee, tea, cocoa, and mint; fruit juices including expelledjuice from washed, scrubbed fruits such as lemon, orange, and lime;spear mint, pepper mint, wintergreen, cinnamon, cacoe/cocoa, vanilla,liquorice, menthol, eucalyptus, aniseeds nuts (e.g., peanuts, coconuts,hazelnuts, chestnuts, walnuts, colanuts), almonds, raisins; and powder,flour, or vegetable material parts including tobacco plant parts, e.g.,genus Nicotiana, in amounts not contributing significantly to the levelof nicotine, and ginger.

[0138] Colouring additives may be selected from dyes being approved as afood additive.

[0139] Stabilizing additives may be selected from the group consistingof antioxidants including vitamin E, i.e., tocopherole, ascorbic acid,sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole,edetic acid and edetate salts; and preservatives including citric acid,tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, andsorbic acid. Preferred embodiments comprise an antioxidant as thestabiliser, and even more preferably the antioxidant vitamin E and/orbutylated hydroxytoluene (BHT).

[0140] Method for Delivering Nicotine in any Form to a Subject

[0141] According to the invention, a method for delivering nicotine inany form to a subject comprises the steps of

[0142] a) administering to a subject a coated chewing gum productcontaining nicotine in any form according to the invention into the oralcavity of the subject, and

[0143] b) allowing the nicotine in any form in the coated chewing gumproduct to be released in the saliva in the oral cavity and absorbedinto the blood plasma of the subject.

[0144] According to the invention, the transmucosal uptake of thenicotine in the oral cavity is more rapid than with presently knownchewing gum not being buffered in the coating. One embodiment results ina t_(max) of nicotine in venous blood of the subject after about 5-20minutes.

[0145] In still one embodiment, said nicotine in any form is absorbedresulting in a t_(max) of nicotine in venous blood of the subject afterabout 3-15 minutes.

[0146] The method for delivering nicotine in any form may furthercomprise the steps of

[0147] c) administering the nicotine in any form in a sustained way overa period of time to the subject.

[0148] Such a time period may be at least 10, 20, 30, 40, 50 or 60minutes.

[0149] Method for Obtaining Reduction of the Urge to Smoke or Use ofTobacco

[0150] A method for obtaining reduction of the urge to smoke or usetobacco containing material and/or for providing a sense of smokingsatisfaction without smoking according to the invention comprises thesteps of

[0151] a) replacing at least partly the tobacco containing material witha coated chewing gum according to any of claims 1-20,

[0152] b) administering to a subject a coated chewing gum productcontaining nicotine in any form according to any of claims 1-20 into theoral cavity of the subject, and

[0153] c) allowing the nicotine in any form in the coating of the coatedchewing gum product to be released in the saliva in the oral cavity andabsorbed by the subject.

[0154] In one embodiment said nicotine in any form results in a t_(max)of nicotine in venous blood of the subject after about 5-20 minutes.

[0155] In a further embodiment, the absorbing of said nicotine releasedfrom the at least one coating layer is resulting in a t_(max) ofnicotine in venous blood of the subject after about 3-15 minutes.

[0156] In still another embodiment, the method according to theinvention further comprises the steps of administering the nicotine inany form in a sustained way over a period of time to the subject.

[0157] The period of time may be at least 10, 20, 30, 40, 50 or 60minutes.

[0158] Even further embodiments of the method for delivering nicotine toa subject may comprise the steps of combining at least one other methodfor obtaining reduction of the urge to smoke or use of tobacco.

[0159] Tobacco containing material may be material used for e.g.,smoking, snuffing or chewing and may comprise a cigarette, a cigarr,snuff, pipe tobacco and also chewing tobacco.

[0160] The coated chewing gum product may be used for obtaining a quickand/or sustained and/or complete reduction of the urge to smoke or useof tobacco and/or for providing a sense of smoking satisfaction withoutsmoking as further discussed below.

[0161] The fast relief provides the subject with a sense of rapidsmoking satisfaction without smoking. Such a satisfaction will decreasethe craving more rapidly than other known nicotine chewing gum products.

[0162] The quick craving relief is obtained when a dosage of nicotine isreleased from at least one of the at least one coating layers of thecoated chewing gum in embodiments wherein nicotine is in the coatinglayers in the presence of one or more buffering agents in the coatingand optionally in the core(s). This provides the subject with an initialrapid transmucosal uptake of nicotine in the oral cavity that willinduce an initial peak, a maximum, in the blood plasma nicotine levelsafter a certain time, t_(max). The result will be that the subject getsa feeling or sense of satisfaction and the initial craving willdisappear.

[0163] One embodiment reduces the urge to smoke or use of tobacco byreaching a t_(max) of nicotine in venous blood of the subject afterabout 5-20 minutes by the use of a coated chewing gum according to theinvention.

[0164] Still one embodiment reduces the urge to smoke or use of tobaccoquickly resulting in a t_(max) of nicotine in venous blood of thesubject after about 3-15 minutes when said nicotine in any form isreleased from the at least one coating layer after use of a coatedchewing gum according to the invention.

[0165] Sustained Reduction of the Urge to Smoke or Use of Tobacco

[0166] Still, to continue the feeling or sense of satisfaction of thesubject, and to avoid that the craving returns, a sustained cravingrelief may be obtained after the initial craving relief. A sustainedcraving relief is obtained by chewing the gum part, or core, of thecoated chewing gum to allow a sustained uptake of the nicotine. Thesustained craving relief and/or feeling or sense of satisfaction of thesubject will continue as long as the subject maintains the blood plasmalevels of nicotine at a level high enough to reach this sense offeeling.

[0167] The subject may achieve this by chewing the gum part of thechewing gum over a period of time, such as 10, 20, 30, 40, 50, or even60 minutes or longer, e.g., a slow release of the nicotine caused by acontrolled release, e.g., by individual chewing.

[0168] Cessation of the Urge to Smoke or Use of Tobacco

[0169] For some of the users, it may be a goal to terminate the usage ofnicotine completely, due to several reasons e.g., health, economical,social or behavioural. This may be achieved by further decreasing theamount of nicotine in any form gradually over time. In a specificembodiment of the invention, the method described above for obtainingcraving relief may further comprise the steps of decreasing the amountof nicotine in the total coated chewing gum product described abovegradually over time, so as to achieve a complete relief of tobaccocraving. This method results in a weaning process gradually over time.

[0170] Different types of smokers reach the sense of reduced craving atdifferent plasma levels of nicotine. This may, of course, affect theindividual types of administration programs of a coated chewing gumaccording to the invention. Different types of smokers include e.g.,peak seekers or smokers that crave for a plasma level of nicotineconstantly being above the level for withdrawal symptoms.

[0171] One strategy may be to lower the frequency of the administeredcoated chewing gums. Other embodiments include varying the dose of thenicotine in said gums as well as the combination of these two. Also, thestrategy may include a coated chewing gum with substantially no nicotinein any form. Such a gum may be administered at the end of the treatmentperiod, when the craving is low or substantially absent.

[0172] Systems for Delivering Nicotine and for Obtaining Craving Relief

[0173] According to the invention there is a system for deliveringnicotine in any form to a subject. Such a system comprises a coatedchewing gum according to the invention and at least one other means forobtaining reduction of the urge to smoke.

[0174] Another system according to the invention may also be a systemfor obtaining reduction of the urge to smoke or use of tobacco and/orfor providing a sense of smoking satisfaction without smoking. Such asystem comprises a coated chewing gum product according to the inventionand at least one other method for obtaining reduction of the urge tosmoke or use tobacco. Other methods may also be a concomitant orconcurrent method selected from the group consisting of administrationthrough mouth sprays, nasal sprays, transdermal patches, inhalingdevices, lozenges, tablets and parenteral methods, subcutaneous methods,intravenous methods, rectal methods, vaginal methods and transmucosalmethods; or use of tobacco.

[0175] In a specific embodiment, the at least other method comprisesadministration of nicotine.

[0176] Use of the Coated Chewing Gum

[0177] The use of the coated chewing gum product according to theinvention is for obtaining a fast and/or sustained and/or completereduction of the urge to smoke and use tobacco or for providing a senseof smoking without smoking as described above.

[0178] The dose of the nicotine is chosen to give the subject anindividual sensory perception and satisfaction with an effect of thenicotine in any form. The use of the coated chewing gum product may alsobe a sole use according to the invention or a combination with othermeans or methods known in the field of drug abuse. Specifically, thepresent invention may be used in combination with other means asdescribed above in the methods in the paragraphs above.

[0179] The use may give a quick reduction of the urge to smoke or usetobacco obtained reaching a t_(max) of nicotine in venous blood aftere.g., about 5-20 minutes.

[0180] In a specific embodiment, the use of the coated chewing gumaccording to the invention will reduce the urge to smoke or use tobaccoby reaching a t_(max), of nicotine in venous blood of the subject afterabout 3-15 minutes when said nicotine in any form is released from theat least one coating layer.

[0181] According to the invention, a use of a coated chewing gum productaccording to the invention is also disclosed for delivering nicotine inany form to a subject.

[0182] In one embodiment, the delivering of nicotine in any form resultsin a t_(max) of nicotine in venous blood of the subject after about 5-20minutes.

[0183] In still another embodiment, the delivering of nicotine in anyform results in a t_(max) of nicotine in venous blood of the subjectafter about 3-15 minutes when said nicotine in any form released fromthe at least one coating layer is absorbed.

[0184] Production of the Coated Chewing Gum

[0185] Coated chewing gum products according to the invention can bemaintained in several production steps depending on the total number ofcores and the total number of coated layers to be included.

[0186] A method for the production of the coated chewing gum accordingto the invention is disclosed.

[0187] The method comprises the steps of

[0188] a) providing at least one chewing gum core, and/or providing atleast one nicotine containing chewing gum core,

[0189] b) providing nicotine in any form,

[0190] c) providing at least one coating layer that is buffered,

[0191] d) adding the nicotine in any form to the at least one chewinggum core and/or to the at least one coating, and

[0192] e) coating the at least one chewing gum core with the at leastone coating layer that is buffered.

[0193] The method may in specific embodiments further comprise

[0194] f) buffering the at least one chewing gum core, and/or

[0195] g) providing at least one coating layer not being buffered, andoptionally

[0196] h) adding the nicotine in any form to at least one of said atleast one coating layer not being buffered, and optionally

[0197] i) providing the nicotine in the coating and the buffer in thecoating in separate layers, preferably separated by a moisture barrier.

[0198] In one embodiment, the nicotine is selected from the groupconsisting of a nicotine salt, the free base form of nicotine, anicotine derivative, such as a nicotine cation exchanger, a nicotineinclusion complex or nicotine in any non-covalent binding; nicotinebound to zeolites; nicotine bound to cellulose or starch microspheres;and mixtures thereof.

[0199] The at least one coating layer may in some embodiments bebuffered by the use a buffer selected from the group consisting of acarbonate buffer, such as the carbonate, bicarbonate, sesquicarbonate ofan alkali metal, e.g., potassium, sodium; or ammonium; sodium glycinate,alkali metal phosphate, sodium or potassium glycerophosphate, trisodiumor tripotassium citrate, and mixtures thereof wherein the at least onecoating layer is buffered in such a way that upon administration of thegum the pH of the saliva is increased by 0.3-4 pH units. The bufferingmay be transient.

[0200] In still further embodiments, the at least one coating layer isbuffered in such way that upon administration of the gum the pH of thesaliva is increased by 0.5-2 pH units. The core/pellet composition maybe formed simply by mixing, rolling and scoring or compression of thechewing gum base with at least one of the forms of nicotine, e.g., thenicotine-ion exchanger complex, or the nicotine as a free base or asalt. Before adding any solid component, except for the gum base, it isdesirable to grind and size the solid component first, to ensure gooddistribution. The mixing is preferably conducted at a suitably elevatedtemperature depending on the viscosity of the gum core used. Theincrease in temperature decreases the viscosity of the gum and therebyenables the nicotine and other additives to be evenly and intimatelydistributed within the core/pellet of the chewing gum.

[0201] Example 5 describes the mixing, rolling and scoring as well asthe compression of gum cores. In principle, this procedure may beapplied for coated chewing gum products up to at least 10 mg unitformula.

[0202] Mixing, rolling and scoring is done by a conventional procedure.Double sigma blade mixers are used for mixing the gum base with theother components of the formulation. The gum base is softened in themixer. By heat (from the heating jacket) and mixing, the gum basebecomes plastic. So, the softened base is mixed with the liquidcomponents, e.g., flavours, liquid, sorbitol and glycerol, nicotine inbase form, when used, and the solid materials, e.g., nicotine in anyform other than in liquid form, buffer, bulk sweetener, colour as apowder mixture. The warm mass is discharged from the mixer in form ofloaves stacked on trays on a truck and stored in a conditioned areauntil the next step starts. This is to cool the gum.

[0203] After this, the rolling and scoring takes place. The gum isextruded into a thick sheet, which is rolled by multiple sets ofcalender rolls to the correct thickness. The scoring rolls, usually twosets, cut the gum into the correct size.

[0204] The sheets are then transferred to a conditioned area on trays,where the sheets are cooled to make them brittle enough to be broken.The conditioned gum sheets are then passed through a breaker, which is arotating drum that parts the sheets into separate pieces of gum alongthe scores.

[0205] At a sorting stage deformed gums are sorted away. The acceptedgums are passed through a metal detector.

[0206] Chewing gums produced by compression, i.e., tabletted gums aremade out of a special gum base. Such a gum base gives a rapid hydrationof the cud in the mouth. High velocity mixers can be used forgranulation to give correctly sized particles of the mixture. Thismixture is then compressed in a tablet machine.

[0207] At a sorting stage deformed gums are sorted away. The acceptedgums are passed through a metal detector.

[0208] In one embodiment of the method disclosed, the provision of theat least one chewing gum core in step a) above comprises the furthersteps of

[0209] a1) providing a gum core dough,

[0210] a2) mixing, rolling and scoring; molding; or extruding the gumdough.

[0211] In still another embodiment, the provision of the chewing gumcore in step a) is obtained by direct compressing of the ingredients.

[0212] Conveniently, the compositions of additives according to theinvention, e.g., the buffer system, are made simultaneously, accordingto known procedures in the art for formulating the buffers. Depending onthe physical properties of the buffer system incorporated, it may beconvenient to add the buffer system/s either with the liquid part orwith he solid part of the composition. In the case of buffering systemsavailable as fine powders, it may, of course, be most convenient to addthose powders with the solid, powdered part of other additives.

[0213] The gum mass with additives is cooled, rolled, scored andhardened sufficiently, and then coated according to the paragraph Thecoating of the gum core/pellet.

[0214] According to the method disclosed in the invention, someembodiments are disclosed where the coating of the at least one chewinggum core with at least one layer of the at least one buffered coatingcomprises the steps of

[0215] a) film coating, and/or

[0216] b) press coating, and/or

[0217] c) sugar coating, and/or

[0218] d) melt coating.

[0219] The product may then be analysed and further wrapped.

[0220] Use for Therapy and Treatment

[0221] The coated chewing gum product according to the invention may beused in therapy. Said therapy may be a treatment of a disease selectedfrom the group consisting of Alzheimer's disease, Crohn's disease,Parkinson's disease, Tourette's syndrome, ulcerous colitis andpost-smoking-cessation weight control.

[0222] The nicotine may also be used for the production of a chewing gumproduct according to the invention for the treatment of a diseaseselected from the group consisting of Alzheimer's disease, Crohn'sdisease, Parkinson's disease, Tourette's syndrome, ulcerous colitis andpost-smoking-cessation weight control.

[0223] Also disclosed is the use of a chewing gum product for theproduction of a nicotine containing chewing gum product according to theinvention for the treatment of a disease selected from the groupconsisting of Alzheimer's disease, Crohn's disease, Parkinson's disease,Tourette's syndrome, and ulcerous colitis.

[0224] Analysis of Nicotine

[0225] The analysis of nicotine uptake and effect according to theinvention may be done according to standard procedure known in the art,e.g., using a bioanalys for the determination of nicotine or itsmetabolites in the plasma of a subject.

EXAMPLES

[0226] The below examples are illustrative and non-limiting.

Example 1 Buffered Sugar Coating

[0227] This example describes without limiting the invention a sugarcoating, wherein the coating is buffered and wherein the nicotine is inthe coating.

[0228] Objective

[0229] The objective of this example is to provide a sugar coatedchewing gum, wherein the coating is buffered and wherein the nicotine isin the coating. The nicotine is in the amount of 1, 2, 4 or 5 mg,respectively.

[0230] Material Sugar Coating*

[0231] A. Nicotine Free Base 1 mg 2 mg 4 mg 5 mg unit unit formula unitformula unit formula formula Component (mg) (mg) (mg) (mg) Sorbitol 19.022.2 28.7 31.9 Mannitol 29.4 29.4 29.4 29.4 Xylitol 162 162 162 162Water q.s.** q.s. q.s. q.s. Gelatin 3.4 3.4 3.4 3.4 Titanium dioxide 2.52.5 2.5 2.5 Sodium carbonate 10 15 20 20 Nicotine free base 1 2 4 5

[0232] B. Nicotine Hydrogen Tartrate 1 mg 5 mg unit formula unit formulaComponent (mg) (mg) Sorbitol 19.0 31.9 Mannitol 29.4 29.4 Xylitol 162162 Water q.s. q.s. Gelatin 3.4 3.4 Sodium carbonate 15 40 Titaniumdioxide 2.5 2.5 Nicotine hydrogen tartrate, N.H.T. 3.1 15.4(corresponding to nicotine free base) 1 5

[0233] Results and discussion

[0234] Other amounts of nicotine are possible.

Example 2 Buffered Film Coating

[0235] This example describes without limiting the invention a filmcoated chewing gum, wherein the coating is buffered and wherein thenicotine is in the coating.

[0236] Objective

[0237] The objective of this example is to provide a film coated chewinggum, wherein the coating is buffered and wherein the nicotine is in thecoating. The nicotine is in the amount of 1, 2, 4 or 5 mg, respectively.

[0238] Material Film Coating

[0239] A. NHT 1 mg unit 4 mg tablet unit formula 2 mg unit formulaformula Component (mg) (mg) (mg) HPMC^(a), 5cPs 15.9 15.9 15.9 20 20PEG^(b) 4000/6000 4.8 0 4.8 0 4.8 Water 27 27 27 34 34 Ethanol 221 221221 278 278 NHT, 3.1 (1) 6.2 (2) 6.2 (2) 12.3 (4) 12.3 (4)(corresponding to nicotine free base, mg) Paraffin wax 0.7 0.7 0.7 0.70.7 Sodium carbonate 15 20 20 35 35

[0240] B. Nicotine Free Base 1 mg 2 mg 4 mg 5 mg unit unit formula unitformula unit formula formula Component (mg) (mg) (mg) (mg) HPMC^(a),5cPs 19.0 19.0 19.0 19.0 PEG^(b) 4000/6000 4.8 4.8 4.8 4.8 Water 27 2727 27 Ethanol 221 221 221 221 Paraffin wax 0.7 0.7 0.7 0.7 Sodiumcarbonate 15 15 20 20 Nicotine free base 1 2 4 5

Example 3 Buffered Press Coating

[0241] This example describes without limiting the invention a presscoated chewing gum, wherein the coating is buffered and wherein thenicotine is in the coating.

[0242] Objective

[0243] The objective of this example is to provide a press coatedchewing gum, wherein the coating is buffered and wherein the nicotine isin the coating. The nicotine is in the amount of 1, 2, 4 or 5 mg,respectively.

[0244] Material Press Coating

[0245] A. NHT 1 mg unit 2 mg unit 4 mg unit 5 mg unit Component formulaformula formula formula Xylitab 100 734 731 725 722 HPMC, 3cPs 238 238238 238 Sodium carbonate 10 20 30 40 Magnesium stearate 10 10 10 10Nicotine hydrogen 3.1 6.2 12.3 15.4 tartrate, corresponding to 1 2 4 4nicotine free base

[0246] B. NRC or NCC 2 mg unit 4 mg unit formula (mg) formula (mg)Component NRC NCC NRC NCC Xylitab 100^(a) 727 720 717 703 HPMC, 3cPs 238238 238 238 Sodium carbonate 15 15 30 30 Magnesium stearate 10 10 10 10NRC 10 — 20 — (corresponding to 2 — 4 — nicotine free base) NCC — 17.1 —34.2 (corresponding to — 2 — 4 nicotine free base)

Example 4 Buffered Melt Coating

[0247] This example describes without limiting the invention a meltcoated chewing gum, wherein the coating is buffered and wherein thenicotine is in the coating.

[0248] Objective

[0249] The objective of this example is to provide a melt coated chewinggum, wherein the coating is buffered and wherein the nicotine is in thecoating. The nicotine is in the amount of 1, 2, 4 or 5 mg, respectively.

[0250] Material Melt Coating

[0251] A. NHT 1 mg unit 2 mg unit 4 mg unit 5 mg unit Component formulaformula formula formula Hydrogenated 176 176 176 176 vegetable oil, typeII, (Akopol E) Cocoa, alkalized 198 197 192 191 Aspartame 2.4 2.4 2.42.4 Sodium carbonate 15 20 30 40 Lecithin 4 4 4 4 Nicotine hydrogen 3.16.2 12.3 15.4 tartrate, (corresponding to 1 2 4 5 nicotine base, mg)

[0252] B. Nicotine Free Base 1 mg unit 2 mg unit 4 mg unit 5 mg unitComponent formula formula formula formula Hydrogenated 176 176 176 176vegetable oil, type II, (Akopol E) Cocoa, alkalized 198 197 192 191Aspartame 2.4 2.4 2.4 2.4 Sodium carbonate 15 15 20 20 Lecithin 4 4 4 4Nicotine free base 1 2 4 5

Example 5 Manufacture of Cores

[0253] This example describes without limiting the invention themanufacture of different cores according to the invention.

[0254] Objective

[0255] The objective of this example is to provide a core suitable for achewing gum product according to the invention. The nicotine isincorporated as the free base (NFB), nicotine β-cyclodextrin complex(NCC), nicotine hydrogen tartrate (NHT) or as a nicotine resin complex(NRC). The amount of nicotine in each fomula unit, i.e., per tablettcore, is 1, 2, 4, or 6 mg.

[0256] Principle

[0257] The core is formed by a mixing, rolling and scoring process or bya compression process.

[0258] Composition of the Cores

[0259] A. Manufactured by Tablet Compression Process. 6 mg 4 mg 2 mg 1mg unit formula unit formula unit formula unit formula (mg) (mg) (mg)(mg) Active ingredients Nicotine resin complex 20% 30 20 10 5 Otheringredients Chewing gum base for 500 500 500 500 compression^(a) Xylitol191 211 221 226 Sorbitol 100 100 100 100 Encapsulated peppermint oil 100100 100 100 Sodium carbonate anhydr. 40 30 20 10 Sodium bicarbonate — —10 20 Magnesium stearate 15 15 15 15 Talcum 15 15 15 15 Magnesium oxide5 5 5 5 Acesulfame K 2 2 2 2 Aspartame 2 2 2 2

[0260] B. Manufactured by Mixing Rolling and Scoring 6 mg 4 mg 2 mg 1 mgUnit formula Unit formula Unit formula Unit formula (mg) (mg) (mg) (mg)Active ingredients Nicotine β-cyclodextrin complex 52.2 34.8 17.4 8.711.5% Other ingredients Chewing gum base^(a) 650 650 650 650 Xylitol 233250 268 276 Peppermint oil 30 30 30 30 Sodium carbonate anhydr. 30 25 2020 Sodium bicarbonate — 5 10 10 Acesulfame K 2 2 2 2 Levomenthol 2 2 2 2Magnesium oxide 1 1 1 1

[0261] C. Manufactured by Mixing Rolling and Scoring 6 mg Unit 4 mg Unit2 mg Unit 1 mg Unit formula formula formula formula (mg) (mg) (mg) (mg)Active ingredients Nicotine free base 6 4 2 1 Other ingredients Chewinggum base^(a) 620 620 620 620 Xylitol 308 310 312 313 Peppermint oil 3030 30 30 Sodium carbonate 30 25 20 10 anhydr. Sodium bicarbonate — 5 1020 Acesulfame K 2 2 2 2 Levomenthol 2 2 2 2 Magnesium oxide 2 2 2 2

[0262] D. Manufactured by Mixing Rolling and Scoring 6 mg Unit 4 mg 2 mgUnit 1 mg formula Unit formula formula Unit formula (mg) (mg) (mg) (mg)Active ingredients Nicotine hydrogen 18.5 12.3 6.2 3.1 tartrate Otheringredients Chewing gum base^(a) 660 660 660 660 Xylitol 246 263 269 272Fruit flavour 30 30 30 30 Sodium carbonate 40 30 20 10 anhydr. Sodiumbicarbonate — — 10 20 Acesulfame K 2 2 2 2 Aspartame 2 2 2 2 Magnesiumoxide 1 1 1 1

[0263] E. Manufactured by Mixing Rolling and Scoring 6 mg 4 mg 2 mg 1 mgUnit formula Unit formula Unit formula Unit formula (mg) (mg) (mg) (mg)Active ingredients Nicotine resin complex 20% 30 20 10 5 Otheringredients Chewing gum base^(a) 660 660 660 660 Xylitol 235 255 265 270Peppermint oil 30 30 30 30 Sodium carbonate anhydr. 40 30 20 10 Sodiumbicarbonate — — 10 20 Acesulfame K 2 2 2 2 Levomenthol 2 2 2 2 Magnesiumoxide 1 1 1 1

[0264] Procedures

[0265] I) Mixing, Rolling and Scoring

[0266] Mixing, rolling and scoring is done by a conventional procedure.Double sigma blade mixers are used for mixing the gum base with theother components of the formulation. The gum base is softened in themixer. By heat (from the heating jacket) and mixing, the gum basebecomes plastic. So, the softened base is mixed with the liquidcomponents, e.g., flavours, liquid, sorbitol and glycerol, when used andthe solid materials, e.g., nicotine in any form, buffer, bulk sweetener,colour) as a powder mixture. The warm mass is discharged from the mixerin form of loaves stacked on trays on a truck and stored in aconditioned area until the next step starts. This is to cool the gum.

[0267] After this, the rolling and scoring takes place. The gum isextruded into a thick sheet, which is rolled by multiple sets ofcalender rolls to the correct thickness. The scoring rolls, usually twosets, cut into the correct size.

[0268] The sheets are then transferred to a conditioned area on trays,where the sheets are cooled to make them brittle enough to be broken.The conditioned gum sheets are then passed through a breaker, which is arotating drum that parts the sheets into separate pieces of gum alongthe scores.

[0269] At a sorting stage deformed gums are sorted away. The acceptedgums are passed through a metal detector.

[0270] II) Compression

[0271] Chewing gums produced by compression (usually being a drymethod), i.e., tabletted gums are made out of a special gum base. Highvelocity mixers can be used for granulation to give correctly sizedparticles of the mixture. This mixture is then compressed in a tabletmachine.

[0272] At a sorting stage deformed gums are sorted away. The acceptedgums are passed through a metal detector.

[0273] All publications and patent documents cited above are herebyincorporated by reference in their entirety for all purposes to the sameextent as if each were so individually denoted.

What is claimed:
 1. A coated chewing gum product comprising at least onebuffered or non-buffered chewing gum core; at least one of nicotine inany form or a nicotine mimicking agent, at least one coating layer andoptionally one or more other additive(s), wherein said coating layer isbuffered.
 2. The product according to claim 1, wherein the at least onechewing gum core is buffered.
 3. The product according to claim 1,wherein the nicotine in any form is a part of the at least one coatinglayer or at least one of the at least one coating layers.
 4. The productaccording to claim 1, wherein the nicotine in any form is a part of thechewing gum core or at least one of the chewing gum cores.
 5. Theproduct according to claim 1, wherein the at least one coating layer isbuffered and upon administration of the gum to a subject the pH of thesaliva of the subject is increased by 0.3-4 pH units.
 6. The productaccording to claim 5, wherein the at least one coating layer is bufferedand upon administration of the gum to a subject the pH of the saliva ofthe subject is increased by 0.5-2 pH units.
 7. The product according toclaim 1 comprising nicotine in any form and a nicotine mimicking agent.8. The product according to claim 1, wherein the at least one coatinglayer is buffered by the use of a buffer selected from the groupconsisting of a carbonate, glycinate, phosphate, glycerophosphate,acetate, gluconate or citrate of an alkali metal, and mixtures thereof,whereby optionally the buffer is microencapsulated, and wherein theoptional buffering of the at least one chewing gum core is obtained bythe use of a buffer selected from the group consisting of a carbonate,glycinate, phosphate, glycerophosphate, acetate, gluconate or citrate ofan alkali metal, and mixtures thereof.
 9. The product according to claim8 wherein the carbonate is monocarbonate, bicarbonate or sesquicarbonateand the alkali metal is potassium, sodium, or ammonium.
 10. The productaccording to claim 1, wherein the nicotine in any form is selected fromthe group consisting of a nicotine salt, the free base form of nicotine,a nicotine derivative, a nicotine inclusion complex or nicotine in anynon-covalent binding, and mixtures thereof.
 11. The product accord toclaim 10 wherein the nicotine derivative is a nicotine cation exchangerand the nicotine in any non-covalent binding is nicotine bound tozeolites, nicotine bound to cellulose or nicotine bound to starchmicrospheres.
 12. The product according to claim 10, wherein thenicotine inclusion complex is a cyclodextrin complex.
 13. The productaccording to claim 12, wherein the cyclodextrin complex isβ-cyclodextrin.
 14. The product according to claim 11, wherein thenicotine cation exchanger is a polyacrylate cation exchanger.
 15. Theproduct according to claim 10, wherein the nicotine salt is a saltformed with tartrate, citrate or malate.
 16. The product according toclaim 1, wherein the nicotine in any form is present in an amount of0.05-10 mg calculated as the free base form of nicotine per piece coatedchewing gum product.
 17. The product according to claim 16, wherein thenicotine in any form is present in an amount of 0.5-6 mg calculated asthe free base form of nicotine per piece coated chewing gum product. 18.The product according to claim 17, wherein the nicotine in any form ispresent in an amount of 2-5 mg calculated as the free base form ofnicotine per piece coated chewing gum product.
 19. The product accordingto claim 3, wherein at least one coating layer comprises nicotine in anyform in an amount of 0-10 mg calculated as the free base form ofnicotine.
 20. The product according to claim 19, wherein at least onecoating layer comprises nicotine in any form in an amount of 0.2-6 mgcalculated as the free base form of nicotine.
 21. The product accordingto claim 20, wherein at least one coating layer comprises nicotine inany form in an amount of 0.5-5 mg calculated as the free base form ofnicotine.
 22. The product according to claim 1, wherein the nicotinemimicking agent is an agent with acrid burning taste.
 23. The productaccording to claim 22, wherein the nicotine mimicking agent iscapsaicin, piperine, zingerone or mixture thereof.
 24. The productaccording to claim 1, wherein the optional one or more additive isselected from the group consisting of stabilisers, softeners, thickeningagents, emulsifiers, glidants, lubricants, sweeteners, flavours,aromatics, enhancers, colouring agents, vitamins, minerals, and mixturesthereof.
 25. The product according to claim 24 wherein the stabilizer isa preservative.
 26. The product according to claim 25 wherein thepreservative is an antioxidant.
 27. The product according to claim 3,wherein in the coating, the nicotine and the buffer are in separatelayers.
 28. The product according to claim 27 wherein said layers areseparated by a moisture barrier, said moisture barrier comprisingsubstances selected from the group consisting of ethylcellulose,hydroxypropyl methylcellulose, polymethacrylates and combinationsthereof.
 29. The product of claim 28 wherein the nicotine is in the formof nicotine hydrogen tartrate and said moisture barrier furthercomprises at least one plasticizer or hydrophobic lipid-based film. 30.The product of claim 28 wherein the nicotine is in the form of nicotinehydrogen tartrate and said moisture barrier further comprises one ormore plasticizers and hydrophobic lipid-based films.
 31. The product ofclaim 29 wherein the lipid-based film comprises stearic acid.
 32. Amethod for delivering nicotine in any form to a subject comprising thesteps of a) administering to a subject a coated chewing gum productaccording to claim 1 into the oral cavity of the subject, and b)allowing the nicotine in any form in the coated chewing gum product tobe released in the saliva in the oral cavity and absorbed into thesystemic circulation of the subject.
 33. The method according to claim32, wherein said administration results in a t_(max) of nicotine invenous blood of the subject after about 5-20 minutes.
 34. The methodaccording to claim 32, wherein said nicotine in any form is a part ofthe at least one coating layer and said nicotine is released from the atleast one coating layer and absorbed, resulting in a t_(max) of nicotinein venous blood of the subject after about 3-15 minutes.
 35. The methodaccording to claim 32, further comprising the step of c) administeringthe nicotine in any form in a sustained way over a period of time to thesubject.
 36. The method according to claim 35, wherein the period oftime is at least 10, 20, 30, 40, 50 or 60 minutes.
 37. A method forobtaining reduction of the urge to use tobacco containing material,comprising the steps of a) replacing at least partly the tobaccocontaining material with a coated chewing gum produt according to claim1, b) administering said coated chewing gum product into the oral cavityof the subject, and c) allowing the nicotine in any form in the coatedchewing gum product to be released in the saliva in the oral cavity andabsorbed by the subject.
 38. The method according to claim 37 whereinsaid method reduces the urge to smoke, provides a sense of smokingsatisfaction without smoking or combinations thereof.
 39. The methodaccording to claim 37, wherein said administration results in a t_(max)of nicotine in venous blood of the subject after about 5-20 minutes. 40.The method according to claim 37, wherein said nicotine in any form is apart of the at least one coating layer and said nicotine is releasedfrom the at least one coating layer and absorbed, resulting in a t_(max)of nicotine in venous blood of the subject after about 3-15 minutes. 41.The method according to claim 37, further comprising the steps ofadministering the nicotine in any form in a sustained way over a periodof time to the subject.
 42. The method according to claim 41, whereinthe period of time is at least 10, 20, 30, 40, 50 or 60 minutes.
 43. Themethod according to claim 37, wherein said method is performed incombination with at least one other method for obtaining reduction ofthe urge to smoke or use tobacco.
 44. A system for delivering nicotinein any form to a subject, comprising a coated chewing gum productaccording to claim 1 and at least one other means or method forobtaining reduction of the urge to smoke or use of tobacco.
 45. Thesystem according to claim 44, wherein the at least one other means ormethod is a concomitant or concurrent means or method selected from thegroup consisting of administration through mouth sprays, nasal sprays,transdermal patches, inhaling devices, lozenges, tablets, parenteralmethods, subcutaneous methods, intravenous methods, rectal methods,vaginal methods, and transmucosal methods.
 46. The system according toclaim 45, wherein the at least other means or method comprisesadministration of nicotine.
 47. A system for obtaining reduction of theurge to smoke or use of tobacco or for providing a sense of smokingsatisfaction without smoking comprising a coated chewing gum productaccording to claim 1 and at least one other means or method forobtaining reduction of the urge to smoke or use of tobacco.
 48. Thesystem according to claim 47, wherein the at least one other means ormethod is a concomitant or concurrent means or method selected from thegroup consisting of administration through mouth sprays, nasal sprays,transdermal patches, inhaling devices, lozenges, tablets, parenteralmethods, subcutaneous methods, intravenous methods, rectal methods,vaginal methods, and transmucosal methods.
 49. The system according toclaim 48, wherein the at least other means or method comprisesadministration of nicotine.
 50. A method for producing a coated chewinggum product according to claim 1, comprising the steps of a) providingat least one chewing gum core, b) providing nicotine in any form, c)providing at least one coating that is buffered, d) adding the nicotinein any form to the at least one of the chewing gum core or the at leastone coating, and e) coating the at least one chewing gum core with atleast one layer of the at least one buffered coating layer.
 51. Themethod of claim 50 wherein said chewing gum core comprises nicotine. 52.The method according to claim 50, further comprising the steps of f)buffering the at least one chewing gum core, g) providing at least onecoating layer not being buffered, and optionally h) adding the nicotinein any form to at least one of said at least one coating layer not beingbuffered, and optionally i) providing the nicotine in the coating andthe buffer in the coating in separate layers, preferably separated by amoisture barrier.
 53. The method according to claim 50, furthercomprising the steps of f) buffering the at least one chewing gum core,or g) providing at least one coating layer not being buffered, andoptionally h) adding the nicotine in any form to at least one of said atleast one coating layer not being buffered, and optionally i) providingthe nicotine in the coating and the buffer in the coating in separatelayers, preferably separated by a moisture barrier.
 54. The methodaccording to claim 50, wherein the nicotine in any form is selected fromthe group consisting of a nicotine salt, the free base form of nicotine,a nicotine derivative, a nicotine inclusion complex or nicotine in anynon-covalent binding, and mixtures thereof.
 55. The method accord toclaim 54 wherein the nicotine derivative is a nicotine cation exchangerand the nicotine in any non-covalent binding is nicotine bound tozeolites, nicotine bound to cellulose or nicotine bound to starchmicrospheres.
 56. The method according to claim 50, wherein the at leastone coating layer is buffered by the use of a buffer selected from thegroup consisting of a carbonate, glycinate, phosphate, glycerophosphateor citrate of an alkali metal, and mixtures thereof, wherein the atleast one coating layer is buffered and upon administration of the gumto a subject the pH of the saliva of the subject is increased by 0.3-4pH units.
 57. The method according to claim 56, wherein the carbonate isbicarbonate or sesquicarbonate and the alkali metal is potassium,sodium, or ammonium.
 58. The method according to claim 57, wherein theat least one coating layer is buffered and upon administration of thegum to a subject the pH of the saliva of the subject is increased by0.5-2 pH units.
 59. The method according to claim 50, wherein theprovision of the at least one chewing gum core in step a) comprises thesteps of a1) providing a gum core dough, a2) mixing, rolling andscoring; moulding; or extruding the gum dough.
 60. The method accordingto claim 50, wherein the provision of the chewing gum core in step a) isobtained by direct compressing of the ingredients.
 61. The methodaccording to claim 50, wherein coating the at least one chewing gum corewith at least one layer of the at least one buffered coating comprisesthe steps of film coating, or press coating, or sugar coating, or meltcoating, or combinations thereof.
 62. A chewing gum product according toclaim 1 for use in therapy.
 63. The product according to claim 62,wherein the therapy is treatment of a disease selected from the groupconsisting of Alzheimer's disease, Crohn's disease, Parkinson's disease,Tourette's syndrome, and ulcerous colitis.
 64. The product according toclaim 62, wherein the therapy is treatment of post-smoking-cessationweight control.
 65. A method of treating a disease selected from thegroup consisting of Alzheimer's disease, Crohn's disease, Parkinson'sdisease, Tourette's syndrome and ulcerous colitis comprising the stepsof administering a chewing gum product of claim 1 to a subject.
 66. Amethod of post-smoking-cessation weight control comprising the steps ofadministering a chewing gum product of claim 1 to a subject.